Pergamon Tetrahedron 54 (1998) 7563-7572

TETRAHEDRON

Acid Catalysed Reactions of 5-Formyluracils with Enamines.

A Facile Synthesis of 5-Acylvinyluracils.

Harjit Singh*, Dolly, Maninder Singh Hundal, Geeta Hundal, Palwinder Singh, Swapandeep Singh Chimni and Subodh Kumar*

Department of Chemistry, Guru Nanak Dev University, Amritsar - 143 005, India

Received 2 March 1998; revised 21 April 1998; accepted 23 April 1998

Abstract: 5-Formyl-l,3-dimethyluracil (1) reacts with secondary amine derived enamines of ketones and aldehydes to provide 5-(acyvinyl)uracil derivatives. The presence of a CH3 group at C-6 of I induces a competitive annulation reaction. Depending on the bulk of substituents 5-(acylvinyl)- uracils acquire cis -diene and E or Z configurations on the vinyl unit. Enamines derived from 1,3-cyciohexanedione and ethyl acetoacetate react with 1 in 1 : 2 stoichiometric manner to provide 5-(9-xanthenyl)uracil and 5-(6- cycohexadienyl)uracil (X-ray) derivatives. © 1998 Elsevier Science Ltd. All rights reserved.

Introduction

In antitumor and anti HSV-1 agents 5-fluorouridine and 5-bromovinyluridine, the presence of highly

electronegative F and Br creates the electron deficiencies which facilitate the attack of a thiol group at C-6 or

vinyl carbon to form a stable enzyme - uracil complex and this phenomenon affects the enzyme function.l3

The presence of stronger electron withdrawing groups at C-5 13-vinyl carbon (fig. 1, B), due to enhanced

Michael acceptor character, would influence the mode of enzyme attack and consequently, there has been

immense interest in the development of synthetic approaches for such 5-(alkenyl)uracils. 49

Recently, we have reported that 5-formyl-l,3-dimethyluracil(1), under acidic conditions, undergoes

annulation reactions with enamines possessing NH2 group (fig.l, R=H). l°AI We envisaged that similar

reactions of enamines possessing tertiary nitrogen (RR--(CH2)n-) would get interrupted at the intermediate

(A) stage and hydrolytic work up would provide 6-acylvinyluracil derivatives (C). It has been found that the

reactions of secondary amine derived enamines of ketones and aldehydes with 1 provide the respective

0040-4020/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved. PII: S0040-4020(98)00390-1

7564 1t. Singh et al. /Tetrahedron 54 (1998) 7563-7572

5-(acylvinyl)uracils but enaminone / ester derived from 1,3-cyclohexanedione / ethyl acetoacetate provides 2:1 stoichiometric 5-(9-xanthenyl) / 5-(6-cyclohexadienyl)uracils.

ooH Me'N I "~

O Me + O

1 O Me. N ~ . . ~ - ' ~ EW

Me

B

0 M e - N ~

R=H O~,. N LN~.. Me Me

(A) ~R=_(CH 2)n" O

Me C

Fig: I

Synthesis:

5-Formyl-l,3-dimethyluracil (1) on reaction with 1-morpholinocyclohexene (2a) in CH3CN-TFA

(100:l) gave a product (50%), m.p. 92 °C, M+(m/z) 248. In its IHnmr the presence of one double triplet 01

=4.4Hz, J2 =l.6Hz) at 8 2.65 due to 2H (-CH2-) and one triplet O = 1.6 Hz) at 5 7.30 (IH) points towards the

olefinic unit possessing H and CH2 substituents trans to each other along with two quartenary carbons (fig. 2,

B). Its ~3C nmr spectrum shows the absence o f a formyl carbon signal and the presence of an olefinic CH at

126.54, a quaternary carbon at $162.36 along with the remaining uracil and cyclohexanone carbon signals, and

0 0 0 Me-N~COCH2Ph M e - N ~

Me ~ 2~ Me

0 0 0 0 0

CH2CH2 O.,,,~,: 3, ~,, ~ ~] I.~ I] IIL...J ~ o- / - .N- v -N- o

m) Me Me 7 Me

~) ~.~ (~) -~CN

2a, n=l 3a, n=l 4 5 2b, n=O 3b, n=0

O O M e ' N ~

Me 8

Fig: 2

H. Singh et al. / Tetrahedron 54 (1998) 7563-7572 7565

support the presence of olefinic unit (D). All these data and the elemental analysis corroborate the structure 6

for this compound. The reaction of I with more reactive l-pyrrolidinocyclohexene (3a) provides 6 (25%) along

with a yellow coloured product (22%), m.p. 262°C, M+(m/z) 398. The latter in its tHnmr spectrum shows a

quintet (5 1.81, 2H), a triplet (5 2.69, 4H) and two downfield 2H singlets at 6 7.32 and 7.57 due to olefinic H

alongwith two 2 x N-Me signals. These spectral data show that this compound is a 2:1 condensation product of

1 with enamine 3a and has been assigned the structure 7. Evidently, the more reactive enamine derived from

an analog of intermediate A (fig. 1) reacts with another molecule of I to form 7.

The reaction of I with I-morpholinocyclopentene (2b) or l-pyrrolidinocyclopentene (3b) affords only

5-vinyluracil derivative 8 (65% and 55%), rap. 166°C, M ÷ m/z 234. Similarly, I with enamine 4 provides 5-

vinyluracil 9 (65%), rap. 155°C, M + m/z 284.

5-Formyl-l,3,6-trimethyluracil (10) on reaction with 1-morpholinocyclohexene (2a) in CH3CN-TFA

solution gives a product (50%), rap. 160-162°C, M*(m/z) 244. In its ~Hnmr spectrum the absence of 6-Me

singlet and the presence of two IH singlets at 6 6.61 and 7.66 along with two multiplets (6 1.75-1.85, 4H;

281-289,4H) and N-Me singlets ( 6 3.45, 3.53) show that 6-CH3 unit of uracil has reacted with carbonyl unit

to constitute an additional CH unit. These data corroborate the structure 12 (fig. 3) for this compound. The

presence of six quaternay carbons, two CH, four CHz and two CH3 carbons in its ~3Cnmr further support this

assignment. Evidently, in these reactions, the initial attack of enamine at CHO carbon is followed by

o o I

Me'N I H

Me ~2b/3b

0 OH

M e" N ~'L,L,L,L,L,L,L,L,~

It

0 0 0 Me. N ~ / ~ . . ~ N.Me

O N M MelN O Me Me

13

-HI~ -H20

Fig: 3

O M e - N ~

g

Me

12

condensation of C6-CH3 with the iminium / carbonyl carbon of cyclohexanone unit. 5-Formyl-l,3,6-

trimethyluracil (10) on reaction with l-morpholinocyclopentene (2b) and 1-pyrrolidinocyclopentene (3b) gives

only 13 (fig. 3), rap. 235-240°C in 30% and 50% yields, respectively. In the latter reactions the corresponding

5-vinyluracil derivative is not isolated. Here, due to the difficulty in formation of relatively strained 5,6

membered ring fused system, the formation of the annulation product is also inhibited.

7566 H. Singh et al. / Tetrahedron 54 (1998) 7563-7572

5-(Substitutedvinyl)uracils, due to extended conjugation with C5-C6 double bond, can exist as trans

and cis diene geometrical isomers and each of these isomers depending on substituents on vinyl unit can exist

as (E)- or (Z)- isomers around the vinyl bond (fig. 4) constituting four geometrical isomers.

0 $ . L 0 L .S 0 0

Me Me Me Me trans-(E)- trans-(Z)- cis-(E)- cis-(Z)-

Fig: 4

In the NOESY spectrum of compound 6, the U-6 olefin H shows two cross peaks at 6 3.5 and 2.5

corresponding to N-Me and CH2 (dt) of cyclohexane unit but there is no cross peak between NMe and CH2

protons. These data point to the cis-(E) configuration for compound 6. Similarly, the NOESY spectrum of 8

shows the interaction of Ur-H with CH2(dt) and NMe signals and should also have cis-(E) structure.

The force field energy minimizations ~2 on different geometrical isomers of 5-vinyluracils 6 and 8 show

that trans-diene derivatives have higher energy and on minimization process are converted to c/s-diene isomers.

During energy minimization, compound 6 shows that cis-(E) and cis-~) configurations do not undergo

isomerisation and the two isomers have small difference in their energies (27 K J/ mol). Similarly, energy

minimization on compound 8 shows that it can exist in two c/s- (E) (-137.84 KJ/mole) and cis-(Z) (-101.09

K J/mole) configurations. In both these cases cis-(E) configurations are more stable than cis-(Z). The energy

minimizations on compound 9 lead to only cis-(E) isomer and unlike 6 and 8, cis-(Z) isomer is not stabilised.

Thus, in case of 5-vinyluracils 6, 8 and 9, the cis-(E) isomers are the most stable ones.

The reaction of I with ethyl 3-morpholinobuten-2-oate (14) provides a yellow compound (25%),

mp. 165-68°C, M ~ m/z 461. Its ~H nmr spectrum shows the presence of one uracil ( NMe - 6 3.32, 3.37, 6-H -

6.64), two ethoxy (6 1.20, 1.24 (t), 4.04, 4.18 (q), one morpholine (NCH2 - 3.00-3.18(m); OCH2 -3.65 -

3.71(m)) and one methyl (2.34) unit. Its proton decoupled off resonance 13C nmr spectrum shows five

quartets, four triplets, four doublets and eight singlets. These data show this compound to be a 1:2

stoichiometric condensation product of I and 14 and in the process one morpholine unit is lost and one CH3 of

enaminone is converted to CH. Also, 6-H of uracil, which in X-ray structure (fig. 6) faces the ~ cloud of

cyciohexadiene, is shifted upfield (/5 6.64) from its normal position (67.0). The ~H -~3C COSY spectrum (table -

1) shows the presence of two sp 2 CH [6101.34 (4.89), 140.35 (6.64)] and two sp 3 CH [644.40(3.65), 35.36

(4.76)] units. These spectral data corroborate structures 15 and 16 for this compound, but the ]H nmr does

not show the coupling between 5'H and 6' H of the cyclohexadiene unit.

H. Singh et a l . / Tetrahedron 54 (1998) 7563-7572 7567

o .COOEt Me'N'J~CHO /~'Me

Me 14 1

,oOOC M e - N ~ M e

" O NJJ - OOEt Me 15

o? o Me"N'J(N'Me EtOOC ~L2' H

M e . N ~ M e o NJj -' oEt "

=~ 18 1 Me

Fig. 5

Fig. 6: SCHAKAL View of Compound 16. The hydrogens of morpholine unit have been eliminated for the sake of clarity.

The single crystal X-ray structure

analysis confirms the structure 15 (fig. 6)

for this compound. Table 2 lists the selected

bond distances and angles of the molecule.

The uracil ring is almost planar (rm.s

deviation 0.02A), the cyclohexadiene ring

possesses half chair conformation and the

morpholine ring shows disorder between

two alternate chair conformations. The

uracil ring is perpendicular to the

cyclohexadiene ring (dihedral angle 88 °)

whereas the morpholine ring makes a

dihedral angle of 51 ° with the

cyclohexadiene ring. The uracil and ester

units on the cyclohexadiene ring remain

trans" to each other and 6-H of uracil faces

the n-cloud of diene unit being placed at

2.26A.

However, 1 reacts with 1 -

morpholinocyclohex-2-enone (17) to give

1:2 stoichiometric product 18 (60%), rap.

279°C, M + m/z 356. Here the ct-CH2 of

the cyclic enamine cannot participate in

cyclisation and two morpholine units are

lost probably during work-up and

subsequent cyclisation leads to 18.

Table-l: [H -~3C correlations in 15 as determined from IH-13C HETCOR NMR spectrum

Signal OCH2 CH3 NCH2 NMe CH CH2 OCH2 CH CH CH CH~ CH~

tH nmr 1.20, 2.34 3.00- 3.32, 3.65- 3.65- 4.04, 4.76 4.89 6.64 1.24 3.18 3.37 3.71 3.71 4.18

L~C nmr 14.09, 21.78 46.37 27.86, 4.40 65.98 59.41, 35.36 101.34 140.35 14.36 37.16 61.24

7568 H. Singh et aL /Tetrahedron 54 (1998) 7563-7572

Table 2. Selective Bond Bond lengths A

ien ,~hs and angles of compound 15. " Bond angles

C(4)-N(1)-C(1) 122.2(4) C(I)-N(2)-C(2) 125.0(4) O(I)-C(I)-N(I) 122.5(4) O(I)-C(1)-N(2) 122.3(4) N(I)-C(I)-N(2) 115.1(4) O(2)-C(2)-N(2) 120.5(4) O(2)-C(2)-C(3) 123.5(4) N(2)-C(2)-C(3) 116.0(4) C(4)-C(3)-C(2) 117.9(4) C(4)-C(3)-C(12) 124.8(4) C(2)-C(3)-C(12) 117.3(4) C(3)-C(4)-N(1) 123.5(4) C(8)-C(7)-C(I 2) I 17. I (6) C(17)-C(7)-C(12) 120.0(4) C(7)-C(8)-C(9) 120.5(5) C(7)-C(8)-C(23) 123.6(6) C(9)-C(8)-C(23) 115.9(5) C(10)-C(9)-C(8) 123.6(5) C(9)-C(10)-N(3) 125.4(5) C(9)-C(10)-C(I 1) 116.3(7) N(3)-C(10)-C(I 1) 118.3(5) C(]0)-C(I 1)-C(20) 111.5(4) C(10)-C(I 1)-C(12) 111.4(4) C(20)-C(11)-C(12) 110.0(4) C(7)-C(12)-C(3) 113.3(4) C(7)-C(12)-C(I 1) 110.3(4) C(3)-C(12)-C(l 1) l 11.3(4)

N(1)-C(4) 1.361(6) N(1)-C(1) 1.374(6) N(2)-C(1) 1.383(6) N(2)-C(2) 1.395(6) N(3)-C(10) 1.394(8) O(l)-C(l) 1.220(6) 0(2)-C(2) 1.226(6) C(2)-C(3) 1.450(6) C(3)-C(4) 1.337(6) C(3)-C(12) 1.516(6) C(7)-C(8) 1.374(7) C(7)-C(12) 1.510(7) C(8)-C(9) 1.425(8) C(9)-C(10) 1.364(8) C(10)-C(I 1) 1.514(7) C(I I)-C(12) 1.555(7)

oo E NO OHx +R. ~ R'

R 2 I~ 2 R'R J

0 X:H

O.:~:L-N ]I O.-']--R, : R2 6-9

(a)

[° 1 I~N I X

I~ 2 R'+R J (b)

Fig: 7

(i)R 3 =R =H Ill

(ii)R3=CH 3, R=H,(CH2)n

Annulation products

1:2 stoichiometric = Products 16/19

From the modes of these reactions, it is evident that enamines initially add to the 5-formyl carbon of 5-

formyl-l,3-dimethyluracil to form intermediate hydroxy-alkyl derivatives (a) (fig.7), which in the case of X,

R3, R=H and X=H, R3 =CH3, R=(CH2), undergo intramolecular cyclization. In the case of X, R3=H, R =

H. Singh et al. /Tetrahedron 54 (1998) 7563-7572 7569

(CH2)~, through acid catalysed dehydration to (b) followed by hydrolytic work up 5-(2'-acylvinyl)uracil

derivatives are formed. However, when in (b), X = CO or COOEt, another enamine molecule adds and

subsequent reactions lead to alternate cyclisation products.

Experimental:

Melting points were determined in capillaries and are uncorrected. ~Hnmr and 13Cnmr spectra were recorded

on Bruker 200 MHz instrument in CDCI3, using TMS as internal standard. Infrared and mass spectra were

recorded on Pye Unicam SP-300 and Shimadzu GC-MS QP2000 (at 70eV) instruments respectively. Reagent

grade CH3CN was freshly distilled over P205. Thin layer chromatography (TLC) was performed on precoated

silica plates. Molecular modelling was performed using DTMM 2.0.

General procedure:

The enamines were prepared by refluxing morpholine or pyrrolidine (leq.) with respective ketones

(leq.) in benzene by azeotropic removal of water using Dean and Stark's apparatus. After complete removal of

water, benzene was distilled off under vacuum. To the enamine residue taken in acetonitrile -TFA mixture

(100:1) (20ml) was added 1,3-dimethyl-5-formyluracil derivatives (leq) and the reaction mixture was refluxed

for 5-6h Acetonitrile was distilled off and the residue was column chromatographed on silica gel using

hexane-ethyl acetate mixtures as eluents. The data for the compounds thus obtained are given below:

Compound 6: (50%), m.p. 92°C (EtOH), M+(m/z) 248, IH nmr (CDCI3): 8 1.72-1.83 (m, 2H, CH2), 1.87-1.95

(m, 2H, CH2), 2.50 (t, J=4Hz, 2H, CH2), 2.65 (dt, J2 = 1.6Hz, Jl = 4.4Hz, 2H = -CH2), 3.37 (s, 3H, NCH3),

3.48 (s, 3H, NCH3), 7.30 (t, J=l.6Hz, C=CH), 7.32 (s, IH,6-H); ~3Cnmr (CDCI3) : 8 23.50 (t, CH2), 23.83 (t,

CH2), 28.24 (q, NCH3), 29.63 (t, CH2),37.54 (q, NCHa), 40.28 (t, CH2), 109.56 (s, C-5), 126.54 (d, C-5-CH),

136.98 (s, qc), 142.65 (d, C-6), 151.40 (s, C=O), 162.36 (s, qc), 182.80 (s, C=O); IR(KBr)vmax:1698 (C=O),

1680 (C=O), 1658 (C=O) cml; ~,max (CH3CN): 318 (e 1.57x10 a) (Found C 62.5, H 66%. Ct3H16N203

requires C 62.90, H 6.45%).

Compound 7 : (22%), m.p.262°C (EtOH), M+(m/z) 398, IHnmr (CDCI3): ~ 1.81 (quintet, J=6Hz, 2H, CH2),

269 (t, J=4Hz, 4H, 2xCH2), 3.39 (s, 6H, 2xNCH3), 3.48 (s, 6H, 2xNCH3), 7.32 (s, 2H, 2xC=CH), 7.57(s, 2H,

2xU6-H); ~3Cnmr(CDCI3): 8 22.61 (t, CH2), 28.69 (q, CH3), 29.44 (t, CH2),109. 06 (qc, s), 127.91 (d, CH),

135.43 (qc, s), 143.45 (d, CH),150.79 (C=O, s), 162.20 (C=O, s), 183.58 (C=O, s). IR(KBR) Vm~x: 1700

(C=O), 1670 (C=O), 1660 (C=O) cm l. (Found C 60.6, H 5.7, N 13.8% C20 H~ N405 requires C 60.30, H

5.53, N 14.07%).

Compound 8: (30%, 65%), m.p.166°C (EtOH), M÷(m/z) 234, ~Hnmr (CDCI3): 5 2.02 (quintet, J = 7.6Hz, 2H,

CH2), 2.3 (t, J=4Hz, 2H, CH2) 2.76 (dt, Jl=7.6Hz, J2=2.6Hz, 2H, CH2), 3.39 (s, 3H, NCH3), 3.49 (s, 3H,

CH3), 7.41 (t, J = 2.6 Hz, 1H, =CH), 7.45 (s, IH, U6-H)., ~3Cnmr (CDCI3): 8 20.03 (t, CH2), 28.24 (q, CH3),

29.79 (t, CH2), 37.53 (t, CH2), 37.66 (q, CH3),110.04 (s, 5-H), 123.21 (d, CH), 1.35.15 (s, C), 142.74 (d,

CH), 150.87 (s, C =O), 162.05 (s, C=O), 206.40 (s, C=O). IR(KBr)v,~:I714 (C-O, ketone), 696 (C=O),

7570 H. Singh et al. / Tetrahedron 54 (1998) 7563-7572

1660 (C=O). kmax (CH3CN) : 327 (e 1.64x104). (Found C 61.6, H 6.0, N 12.0% CI2HI4N203 requires C

61.54, H 5.98, N I 1.97%).

5-(2-Phenylacetylvinyl)-l,3-dimethyluracil (9): (65%), mp.155°C (EtOH), M+(m/z) 284, 1Hnmr (CDCI3): 8

3.36 (s, 3H, NCH3), 3.45 (s, 3H, NCH3), 3.85 (s, 2H, CH2), 7.19-7.36 (m, 7H, C=CH, ArH), 7.45 (s, IH, U6-

H).~3C nmr: 8 28.17 (q, NCH3), 37.51 (q, NCH3), 49.33 (t, CH2), 108.31 (s, C-5), 125.30 (d, CH), 126.95 (d,

CH), 128.72 (d, CH), 129.58 (d, CH), 134.46 (s), 135.09 (d, =CH), 145.86 (d, CH),150.66 (s, C=O), 161.43

(s, C=O), 197.75 (s, C=O). IR (KBr)v,~: 1710 (C~O), 1665 (C=O) ,1650 (C=O) cm ~. ~,max: 317 (e

2.38xl04). (Found C 67.3, H 5.5, N 9.9%. C16HI6N203 requires C 67.61, H 5.63, N 9.86%).

1,3-Dimethyl-6, 7, 8, 9-tetrahydronaphtho[2,3-e]pyrimidine-2, 4(1H,3H)dione (12): (50%), m.p. 160-162°C

(EtOH), M+(m/z) 244, ~Hnmr (CDCI3): 8 1.75-1.85 (m, 4H, 2xCH2), 2.81-289 (m, 4H, 2xCH2), 3.45 (s, 3H,

NCH3), 3.53 (s, 3H, NCH3), 6.61 (s, lH, =CH), 7.66 (s, IH, =CH); ~3Cnmr (CDCI3): 8 22.72 (-ve, CH2),

22.94 (-ve, CH2), 26.33 (+ve, NCH3), 30.33 (+ve, NCH3), 113.24 (+ve, CH), 128.79 (+re, CH), 132.35

(absent), 1380 (absent), 145.32 (absent), 151.17 (absent), 161.83 (absent)171.82; IR (KBr) vm~x : 1650

(C=O), 1701 (C=O) cm l. (Found C 68.7, H 6.5, N 11.1%, CI4HI6N202 requires C 68.85, H 6.56, N I 1.48%).

Compound 13: (30%), mp.235-240°C (EtOH), M+(m/z) 412, IHnmr (CDCI3): 8 2.29 (s, 6H, 2xCH3), 2.55

(s, 4H, 2xCH2), 3.46 (s, 6H, 2xNH3), 3.50 (s, 6H, 2xNCH3), 7.26 (s, 2H, =CH), 13Cnmr (CDCla)(Normal /

DEPT-135): 8 17.95 (+re, CH3), 26.45 (-ve, CH2), 26.93 (+ve, NCH3), 32.42 (+ve, NCH3), 12600 (+re, CH),

140.1 (absent), 142.47 (absent), 143.65 (absent), 150.62 (absent), 151.65 (absent), 160.05 (absent); IR (KBr)

Vma~ : 1650 (C=O), 1710 (C=O) cm l. (Found C 61.0, H 6.1, N 13.8%. C21H24N405 requires C 61.17, H 5.82,

N 13.59%)

Compound 15: (25%), rap. 165-68°C, M + m/z 461; IH nrnr(CDCI3): 8 120 (t, J 7Hz, 3H, CH~), 1.24(t, J

7Hz, 3H, CH3), 2.34(s, 3H, CH3), 3.00-3.18(m, 4H, z 2 x NCH2), 3.32(s, 3H, NCHa), 3.37(s, 3H, CHQ, 3.65-

3.71(m, 5H, 1H+ 2 x OCH2), 4.04 (q, J 7Hz, 2H, OCH2), 4.18 (q, J 7Hz, 2H, OCH2), 4.76(s, IH, CH), 4.89(s,

1H, CH), 664(s, IH, CH); ~3C nmr (normal / proton decoupled off resonance): 8 14.09(+ve, CH3), 14.36(q,

CH3), 21.78(q, CH3), 27.86( q, CH3), 35.36( d, CH), 37.16(q, CH3), 44.40(d, CH), 46.37 (t, CH2), 59.41(t,

CH2), 61.24(t, CH2), 65.98(t, CH2), 101.34(d, CH), 108.42(s, C), 109.62(s, C), 140.35 (d, CH), 149.19 (s, C),

15086(s, C), 151.60(s, C), 163.32(s, C), 166.73(s, C), 170.41(s, C). (Found C 60.1, H 6.9, N 8.9%.

C23H3tN.~O7 requires C 59.87, H 6.72, N 9.11%).

1,8-Dioxo-(1,3-dimethyluracil-$yl)-l,2,3,4,5,6,7,8-octahydroxanthene (18): (60%), rap. 279°C (EtOH),

M+(m/z) 356; ~Hnmr (CDCI3): 8 1.93-2.07 (m, 2H, CH2), 2.23-2.78 (m,8H, 4xCH2), 3.22 (s, 3H, NCH3), 3.39

(s, 3H, NCH3), 4.44 (s, 1H, 9-H), 7,49 (s, lH, U-6H); ~3C nmr (CDCI3): 8 20.16 (t, CH2). 27.74 (t, CH2),

27.33 (q, CH3), 27.30 (d, CH), 36.80 (t, q, CH2, CH3), 110.83 (s, C), l l2.10 (s, C), 143.05 (d, =CH), 151.39

(s, C=O), 162.01 (s, C=O), 166.37 (s, qc), 197.41 (s, C=O). IR(KBr)v~x: 1720 (C=O), 1670(C=O) cm~;

H. Singh et al. / Tetrahedron 54 (1998) 7563-7572 7571

Lmax: 284 (e 1.14x104), 230 (2.13x104) (Found C 64.3, H 5.9, N 7.9% C19H20N205 requires C 64.04, H 5.62,

N 7.86%).

Crysta l s tucture d e t e r m i n a t i o n : ~3 Needle shaped yellow crystals of 0.3 x 0.2 x 0.1 mm, Siemens P4

diffractometer, cell constants from least square fit of setting angles of 25 reflections with 20 range 15-25 °, w -

2 0 scan, 2 0(max) 45 °, graphite monochromatized Mo Kct radiation, index range 0 _< h -< 10, 0 _< k <_ 8, -22 _< I

<_ 21,2661 reflections collected, 2514 independent reflections (Rint. = 0.0244), 2304 considered observed [ I 2

2s (I)]. Three standard reflections measured every 100 reflections. Corrections for Lorentz - polarization

effects but none for absorption. The structure was solved by direct methods. Anisotropic refinement based on

F 2 revealed two very short C13-C14 and C15-C16 distances (1.212 and 1.217 A ) with nearly eclipsed torsion

angles in the morpholine ring and very large U components of the temperature factor for four C and one O

atoms in morpholine ring, indicating disorder in the two C-C bonds and 03 atom.

During subsequent refinement the bond lengths involving these C atoms, which were assigned isotropic,

U values were restrained to realistic values (C-C 1.520(5), C-O 1.440(5) and C-N 1.470(5) A) and the site

occupation factor (s.o.f.'s) of the C atoms were fixed at 0.70. After refinement, the difference Fourier maps

yielded one satellite peak near each of the four disordered C atoms. Because of the satisfactory geometry, these

peaks were refined with the same restraints as above. The occupation factors of the C atoms of the disordered

C-C bonds converged to 0.64 for C131-C 141 and C 15 I-C 161. A similar treatment with 03 did not show any

satellite peak although the thermal parameter for this atom was also high and 03 was not treated as a

disordered atom, only C-O bond lengths were restrained as stated above. In the final stages of refinement, these

four C atoms were also made anisotropic by means of applying rigid bond restraints, which restrained the

differences in the components of the displacement parameters of the two atoms to zero along 1,2- and 1,3-

vector directions introducing four extra restraints. All the hydrogen atoms were fixed geometrically including

those attached to the disordered C atoms and they were made to ride on their respective C atoms. All the bond

distances and angles were obtained within a satisfactory range except for C21-C22 which was on a shorter side

(1.340 •). As these terminal atoms show relatively large thermal parameters, this bond was also restrained to

a realistic value of C-C = 1.520(5) A. The final full matrix least squares anisotropic refinement of all the 39

non-hydrogen atoms with 17 restraints and 334 parameters converged to R1 = 0.07, Rw = 0.19 for the

observed data and R1 = 0.09, Rw = 0.23 for all the data, with w = 1, GOOF = 1.069, Max. and min. electron

densities 0.489 and -0.324 e A "3 in the final difference Fourier map. w = 1 [s ~ (Fo) 2 +(0.1416p) 2 + 1.5124p]

where p = (Fo 2 +2F~2)/3.

Acknowledgements: The financial assistance from UGC (India) is greatfully acknowledged.

7572 H" Singh et al. /Tetrahedron 54 (1998) 7563-7572

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